Follicular lymphoma is the second most common type of non-Hodgkin's lymphomas in the West. In the early stage, this tumor is usually indolent and susceptible to chemotherapy or radiotherapy. However, virtually all patients undergo blast transformation, becoming refractory to the currently available treatment. Our long- term goal is to develop a novel therapeutic strategy to eradicate lymphoma cells by blocking the protumorigenic factors provided by the microenvironment in combination with the conventional therapies because the cellular microenvironment within lymphoma appears to confer drug resistance. B cell lymphomas originate from the specialized tissue, the germinal center (GC) of the lymphoid follicles. Follicular dendric cells (FDC) are the stromal cells forming the microenvironment of the germinal center. The specific hypothesis is that FDC provide essential molecules for survival and growth of the drug-resistant lymphoma cells. This hypothesis is based on the observations that: A) the generation and transformation of lymphomas occurs in close association with FDC;B) some human B cell lymphoma cell lines require FDC to proliferate in vitro and form tumors in vivo;C) a FDC signaling molecule (CD320) critical for lymphoma cell proliferation has been identified;and D) a monoclonal antibody (anti-CD320) suppresses growth of lymphoma cells in vitro and in vivo. The specific aims are: 1) To develop a novel therapeutic strategy using anti-CD320 in combination with anti-CD20 (Rituximab). Anti-CD320 blocks the crucial growth factor from FDC while Rituximab targets B cell lymphoma directly. Since anti-CD320 significantly inhibited lymphoma formation, the effect of the combination therapy will be evaluated at different stages of tumor formation to establish the optimum protocol. 2) To analyze genetic changes of lymphoma cells in the course of blast transformation under the influence of FDC by DNA microarray method to identify genes responsible for malignant transformation. A few important genes will be functionally validated using neutralizing monoclonal antibodies and small interfering RNAs. 3) To identify receptors for a novel protein CD320 using (1) proteomic method and (2) mammalian expression cloning method. The identified receptor will be validated by the protein-protein interaction and functional assays. Since we propose to develop a combination therapy against both lymphoma and lymphoma-fostering microenvironment, the proposed experiments will provide important information in the development of a new therapeutic approach. Our inducible lymphoma model in vivo offers unprecedented opportunities to evaluate the efficacy of the combined therapy and the genetic analysis of malignant transformation of lymphoma cells.